Abstract
Breast cancer is a heterogeneous disease and the leading cause of female cancer mortality worldwide. About 70% of breast cancers express ERα. HOX proteins are master regulators of embryo development which have emerged as being important players in oncogenesis. HOXA1 is one of them. Here, we present bioinformatic analyses of genome-wide mRNA expression profiles available in large public datasets of human breast cancer samples. We reveal an extremely strong opposite correlation between HOXA1 versus ER expression and that of 2,486 genes, thereby supporting a functional antagonism between HOXA1 and ERα. We also demonstrate in vitro that HOXA1 can inhibit ERα activity. This inhibition is at least bimodal, requiring an intact HOXA1 DNA-binding homeodomain and involving the DNA-binding independent capacity of HOXA1 to activate NF-κB. We provide evidence that the HOXA1-PBX interaction known to be critical for the transcriptional activity of HOXA1 is not involved in the ERα inhibition. Finally, we reveal that HOXA1 and ERα can physically interact but that this interaction is not essential for the HOXA1-mediated inhibition of ERα. Like other HOX oncoproteins interacting with ERα, HOXA1 could be involved in endocrine therapy resistance.
Highlights
Breast cancer is the most diagnosed female cancer and the leading cause of cancer mortality among women worldwide [1]
We previously identified a causal role between HOXA1 expression and NF-kB pathway activation in breast cancer [32]
To further explore an oncogenic role for HOXA1 in breast cancer, we examined HOXA1 mRNA expression in public genome-wide mRNA expression datasets of human breast cancer samples (Table 3)
Summary
Breast cancer is the most diagnosed female cancer and the leading cause of cancer mortality among women worldwide [1]. The four commonly accepted molecular breast cancer subtypes are luminal A, luminal B, HER2-enriched, and basal-like tumors. Three main molecular markers are used to characterize these: ER (estrogen receptor), PR (progesterone receptor), and HER2 (human epithelial growth factor receptor) expression. Therapeutic antibodies targeting HER2 can inhibit tumor growth, but often resistance develops to this treatment. Basal-like cancers do not express any of the three markers, ER, PR, and HER2, and are considered to be the most aggressive breast cancers. They are characterized by cytokeratin 5 and 17 as well as EGFR expression. Basal-like breast cancers are sometimes grouped as triple-negative breast cancers (TNBCs), but TNBCs do not share all basal-like characteristics [5]
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